Cellular Mechanisms in Neuronal Migration

Despite prominent differences in the distance covered by distinct neuronal types until their final settlement in the brain, or even fundamental discrepancies in the primary mode of migration used by different populations of neurons (discussed in detail in the next section), migrating neurons appear to use a basic set of cellular mechanisms that is roughly similar to those used by other cell types during vertebrate morphogenesis. In that sense, neuronal migration can be considered a cyclic process, in which polarization of the cell is followed by the extension of cell protrusions and differential rearrangements in the adhesion properties of the plasma membrane leading to the movement of the neuron, including its nucleus (nucleokinesis). Moreover, because cell migration is fundamental not only during vertebrate development, but also to plants and even single-celled organisms, the molecular mechanisms underlying this process are likely to be highly preserved throughout evolution.

1.11.2.1 Polarization of Migrating Neurons

The initial response of an immature neuron to a migration-promoting factor is similar to that of other cell types in different organs and organisms and includes the polarization and extension of protrusions in the direction of migration. In other words, the molecular processes occurring at the front and the back of a neuron become distinct during migration, although we still do not understand the fundamentals of these differences. In migrating neurons, the polarized protrusion in the direction of movement is known as the leading process, which appears to behave similarly to extending axons during axon growth and guidance. As growing axons, migrating neurons typically have a single leading process that constitutes the compass reading structure driving directed neuronal migration. In some cases, however, such as, for example, immature cortical interneurons, two or more leading processes seem to act coordinately to direct cell movement (Marin and Rubenstein, 2001). Moreover, although the leading process in migrating neurons is typically only a few cell diameters in length, an extremely long leading process (up to more than 1 mm long) characterizes some populations of migrating neurons. This is the case for example of basilar pontine neurons, which are born in the dorsal hindbrain and migrate to the ventral midline, where they finally reside (Yee et al., 1999).

Despite the close resemblance of the leading process - in particular, of long leading processes - to growing axons, marker analysis suggests that these two structures are molecularly different to a large extent, bearing strong similarities only at their more distant tip, the growth cone (Ramony Cajal, 1911). For example, the processes of basilar pontine neurons stain with antibodies against transiently expressed axonal surface glycoprotein-1 (TAG-1), but do not express any of the common neuronal markers associated with axons, including growth-associated protein 43 (a molecule expressed by immature axons), microtubule-associated protein-2, or neurofilament 200. Thus, leading processes and growing axons seem to represent distinct cellular specializations used by neurons at different stages of development (Figure 1).

The polarization of migrating neurons (i.e., the extension of a leading process) depends on chemo-tactic responses to external cues, which seem to control also the orientation of the leading process and therefore the subsequent direction of movement. The molecules that influence the behavior of migrating neurons also typically control axon path-finding, suggesting that the mechanisms underlying the polarization of both migrating neurons and axons are very similar. For example, Netrin-1, a prototypical axon guidance molecule (Serafini et al., 1994), also promotes the extension of leading processes during neuronal migration and influences the direction of migration in multiple neuronal populations through the CNS. Similarly, Slit proteins prevent axon growth into undesirable regions

Trailing Leading process process

Microtubules--

Trailing Leading process process

Microtubules--

(2) Nucleus translocates forward

(3) Trailing process remodeling

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